Fluorinated 4-(substituted amino)phenyl carbamate derivatives

ABSTRACT

The application relates to 4-(substituted amino)phenyl carbamate derivatives, or pharmaceutically acceptable salts or solvates thereof, as KCNQ2/3 potassium channel modulators, and methods of their uses.

RELATED APPLICATION

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 62/597,979, filed on Dec. 13, 2017, the entire contentsof which are incorporated herein by reference.

BACKGROUND

Epilepsy is one of the most common chronic neurological disorders, andaffects approximately 50 million people worldwide. Epilepsy patientshave significantly increased morbidity, including closed head injury,fractures, burns, dental injury and soft tissue injury. Decline in orworsening of memory, cognition, depression and sexual function and otherlifestyle limitations occur frequently in epilepsy patients. Epilepsypatients also have an increased risk of mortality compared to thegeneral population.

Although various pharmacologic agents are approved to treat epilepsy,many patients are not adequately treated with the currently availableoptions. It is estimated that nearly a third of patients with epilepsyhave either intractable or uncontrolled seizures or significant adverseside effects.

Ezogabine or retigabine, also known as ethylN-[2-amino-4-[(4-fluorophenyl) methylamino]phenyl]carbamate, is ananticonvulsant used as a treatment for partial epilepsies. Ezogabineworks primarily as a potassium channel opener, i.e., by activatingKCNQ2/3 voltage-gated potassium channels in the brain. Ezogabine wasapproved by the FDA and is marketed as Potiga™ and Trobalt™. U.S. Pat.No. 5,384,330 and WO 01/01970 describe ezogabine and its use. The mostcommon adverse events with ezogabine are central nervous system effects,particularly dizziness and somnolence. Occasional instances of urinarydifficulty may require surveillance. Recently, ezogabine has beenassociated with skin discoloration and eye pigmentation changes inpatients. These more serious side-effects have resulted in the marketingapplication holders and its removal from the market in 2017.

Because of the beneficial activities seen with ezogabine, there is acontinuing interest in developing new compounds to treat epilepsy andother conditions ameliorated by KCNQ2/3 potassium channel opening.

SUMMARY OF THE APPLICATION

The present application relates to a compound of formula A:

or a pharmaceutically acceptable salt or solvate thereof, wherein thecompound of formula A is disclosed in detail herein below.

The application also relates to a pharmaceutical composition comprisinga compound of the present application, or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

The application also relates to a method of modulating a KCNQ2/3potassium channel, comprising administering to a subject in needthereof, a therapeutically effective amount of a compound of the presentapplication, or a pharmaceutically acceptable salt or solvate thereof.

The application also relates to a compound of the present application,or a pharmaceutically acceptable salt or solvate thereof, for use inmodulating a KCNQ2/3 potassium channel.

The application also relates to a compound of the present application,or a pharmaceutically acceptable salt or solvate thereof, for use in themanufacture of a medicament for modulating a KCNQ2/3 potassium channel.

The present application also relates to use of a compound of the presentapplication, or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for modulation of a KCNQ2/3 potassiumchannel.

The application further relates to a method of treating or preventing adisease or disorder which can be ameliorated by KCNQ2/3 potassiumchannel opening, comprising administering to a subject in need thereof,a therapeutically effective amount of a compound of the presentapplication, or a pharmaceutically acceptable salt or solvate thereof.

The application also relates to a compound of the present application,or a pharmaceutically acceptable salt or solvate thereof, for use intreating or preventing a disease or disorder which can be ameliorated byKCNQ2/3 potassium channel opening.

The application also relates to a compound of the present application,or a pharmaceutically acceptable salt or solvate thereof, for use in themanufacture of a medicament for treating or preventing a disease ordisorder which can be ameliorated by KCNQ2/3 potassium channel opening.

The present application also relates to use of a compound of the presentapplication, or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for the treatment or prevention of adisease or disorder which can be ameliorated by KCNQ2/3 potassiumchannel opening.

The application further relates to a method of treating or preventingepilepsy, comprising administering to a subject in need thereof, atherapeutically effective amount of a compound of the presentapplication, or a pharmaceutically acceptable salt or solvate thereof.

The application also relates to a compound of the present application,or a pharmaceutically acceptable salt or solvate thereof, for use intreating or preventing epilepsy.

The application also relates to a compound of the present application,or a pharmaceutically acceptable salt or solvate thereof, for use in themanufacture of a medicament for treating or preventing epilepsy.

The present application also relates to the use of a compound of thepresent application, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for the treatment orprevention of epilepsy.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the case of conflict, thepresent specification, including definitions, will control. In thespecification, the singular forms also include the plural unless thecontext clearly dictates otherwise. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present application, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference. The references cited herein are not admitted to be prior artto the present application. In addition, the materials, methods, andexamples are illustrative only and are not intended to be limiting.

Other features and advantages of the application will be apparent fromthe following detailed description and claims.

DETAILED DESCRIPTION OF THE APPLICATION

For purposes of the present application, the following definitions willbe used (unless expressly stated otherwise):

The term “a compound of the application” or “compounds of theapplication” refers to any compound disclosed herein, e.g., a compoundof any of the formulae described herein, including formula A, Ia, Ib,IIa, IIb, IIIa, IIIb, IVa, or IVb, and/or an individual compoundexplicitly disclosed herein. Whenever the term is used in the context ofthe present application it is to be understood that the reference isbeing made to the free base, a deuterium labeled compound, and thecorresponding pharmaceutically acceptable salts or solvates thereof,provided that such is possible and/or appropriate under thecircumstances.

The term “pharmaceutical” or “pharmaceutically acceptable” when usedherein as an adjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipient, and salt must be compatible with the activeingredient of the formulation (e.g., a compound of the application). Itis understood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

Some of the compounds of the present application may exist in unsolvatedas well as solvated forms such as, for example, hydrates.

“Solvate” means a solvent addition form that contains either astoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. In the hydrates, the water moleculesare attached through secondary valencies by intermolecular forces, inparticular hydrogen bridges. Solid hydrates contain water as so-calledcrystal water in stoichiometric ratios, where the water molecules do nothave to be equivalent with respect to their binding state. Examples ofhydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.Equally suitable are the hydrates of salts of the compounds of theapplication.

Physiologically acceptable, i.e., pharmaceutically compatible orpharmaceutically acceptable, salts can be salts of the compounds of theapplication with inorganic or organic acids. Preference is given tosalts with inorganic acids, such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid, or to salts withorganic carboxylic or sulphonic acids, such as, for example, aceticacid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid,malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, ormethanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid,toluenesulphonic acid or naphthalenedisulphonic acid. Otherpharmaceutically compatible salts which may be mentioned are salts withcustomary bases, such as, for example, alkali metal salts (for examplesodium or potassium salts), alkaline earth metal salts (for examplecalcium or magnesium salts) or ammonium salts, derived from ammonia ororganic amines, such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietylamine or methylpiperidine. Representative salts includethe following: acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamottle (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

The compounds of the application may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers. It is intended that allof the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthe application. The application is meant to comprehend all suchisomeric forms of these compounds.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine. In one example,

are tautomers to each other.

It is to be understood that the compounds of the present application maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present application, and the namingof the compounds does not exclude any tautomer form.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as contacting a racemicmixture of compounds with an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The diastereomeric mixture is often a mixture ofdiasteriomeric salts formed by contacting a racemic mixture of compoundswith an enantiomerically pure acid or base. The diastereomericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which are well known in the art.

The application also includes one or more metabolites of a compound ofthe application.

The present application also comprehends deuterium labeled compounds ofeach of the formulae described herein or the individual compoundsspecifically disclosed, wherein a hydrogen atom is replaced by adeuterium atom. The deuterium labeled compounds comprise a deuteriumatom having an abundance of deuterium that is substantially greater thanthe natural abundance of deuterium, e.g., 0.015%.

The term “deuterium enrichment factor” as used herein means the ratiobetween the deuterium abundance and the natural abundance of adeuterium. In one aspect, a compound of the application has a deuteriumenrichment factor for each deuterium atom of at least 3500 (52.5%deuterium incorporation at each deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium), at least 5500 (82.5% deuteriumincorporation), at least 6000 (90% deuterium incorporation), at least6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuteriumincorporation), at least 6600 (99% deuterium incorporation), or at least6633.3 (99.5% deuterium incorporation).

Deuterium labeled compounds can be prepared using any of a variety ofart-recognized techniques. For example, deuterium labeled compounds ofeach of the formulae described herein or the compounds listed in Table 1can generally be prepared by carrying out the procedures describedherein, by substituting a readily available deuterium labeled reagentfor a non-deuterium labeled reagent.

A compound of the application or a pharmaceutically acceptable salt orsolvate thereof that contains the aforementioned deuterium atom(s) iswithin the scope of the application. Further, substitution withdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life and/or reduced dosage requirements.

As used herein, the term “treat”, “treating”, or “treatment” herein, ismeant decreasing the symptoms, markers, and/or any negative effects of adisease, disorder or condition in any appreciable degree in a patientwho currently has the condition. The term “treat”, “treating”, or“treatment” includes alleviating symptoms of a disease, disorder, orcondition, e.g., alleviating the symptoms of epilepsy. In someembodiments, treatment may be administered to a subject who exhibitsonly early signs of the condition for the purpose of decreasing the riskof developing the disease, disorder, and/or condition.

As used herein, the term “prevent”, “prevention”, or “preventing” refersto any method to partially or completely prevent or delay the onset ofone or more symptoms or features of a disease, disorder, and/orcondition. Prevention may be administered to a subject who does notexhibit signs of a disease, disorder, and/or condition.

As used herein, “subject” means a human or animal (in the case of ananimal, more typically a mammal). In one embodiment, the subject is ahuman. In one embodiment, the subject is a male. In one embodiment, thesubject is a female.

As used herein, the term a “fluorinated derivative” is a derivativecompound that has the same chemical structure as the original compound,except that at least one atom is replaced with a fluorine atom or with agroup of atoms containing at least one fluorine atom.

The problem to be solved by the present application is theidentification of novel compounds for the treatment and/or prevention ofepilepsy and/or other diseases or disorders ameliorated by KCNQ2/3potassium channel opening. Although drugs for epilepsy and relateddisorders are available, these drugs are often not suitable for manypatients for a variety of reasons. Many epilepsy drugs are associatedwith adverse effects. For example, many of the available epilepsy drugsare believed to significantly increase the risk of birth defects iftaken during the first trimester of pregnancy. Other adverse sideeffects include urinary retention, neuro-psychiatric symptoms includinghallucinations and psychosis, dizziness and somnolence, QT-prolongingeffect, and increased risk of suicidal behavior and ideation. Someepilepsy drugs require administration of high doses due to extensivemetabolism into inactive or less potent metabolites. The presentapplication provides the solution of new fluorinated 4-(substitutedamino)phenylcarbamate compounds for treating epilepsy and other diseasesor disorders ameliorated by KCNQ2/3 potassium channel opening. Thecompounds described herein have the advantage of providing improvedpotency, selectivity, tissue penetration, half-life, and/or metabolicstability.

Compounds of the Application

The present application relates to a compound of formula A:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X₁ and X₉ are each independently methyl or ethyl;

X₄ is H, C₁-C₄ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

X₅ is phenyl-(CX₈X₈)_(m), wherein the phenyl is optionally substitutedwith one or more substituents independently selected from deuterium, F,SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one or more F, C₁-C₄alkoxy, and C₁-C₄ alkoxy substituted with one or more F; or

X₄ and X₅, together with the nitrogen atom to which they are attached,form a 5- to 7-membered heterocyclic ring comprising 1 or 2 heteroatomsselected from N, O, and S, wherein the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one or moreF, C₁-C₄ alkoxy, and C₁-C₄ alkoxy substituted with one or more F, or twosubstituents attached to adjacent carbon atoms on the heterocyclic ring,together with the carbon atoms to which they are attached, form a phenyloptionally substituted with one or more substituents independentlyselected from deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substitutedwith one or more F, C₁-C₄ alkoxy, and C₁-C₄ alkoxy substituted with oneor more F;

each X₅ is independently H, deuterium, F, C₁-C₄ alkyl, or C₁-C₄ alkylsubstituted with one or more F; and

m is 1, 2, or 3.

In one embodiment, the compound of formula A is of formula Ia:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₄,X₅, X₈, and m are each as defined above in formula A.

In one embodiment, the compound of formula A is of formula Ib:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₄,X₅, X₈, and m are each as defined above in formula A.

For a compound of formula A, Ia, or Ib, X₁, X₄, X₅, X₈, X₉, and m caneach be, where applicable, selected from the groups described hereinbelow, and any group described herein for any of X₁, X₄, X₅, X₈, X₉, andm can be combined, where applicable, with any group described herein forone or more of the remainder of X₁, X₄, X₅, X₈, X₉, and m.

In one embodiment, X₁ and X₉ are each methyl.

In one embodiment, X₁ and X₉ are each ethyl.

In one embodiment, one of X₁ and X₉ is methyl and the other is ethyl.

In one embodiment, X₄ is H.

In one embodiment, X₄ is C₁-C₄ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In one embodiment, X₄ is selected from methyl, ethyl, propyl, i-propyl,butyl, i-butyl, and t-butyl.

In one embodiment, X₄ is selected from ethenyl, propenyl (e.g.,1-propenyl or 2-propenyl), butenyl (e.g., 1-butenyl, 2-butenyl, or3-butenyl), pentenyl (e.g., 1-pentenyl, 2-pentenyl, 3-pentenyl, or4-pentenyl), and hexenyl (e.g., 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, or 5-hexenyl). In one embodiment, X₄ is 1-propenyl or2-propenyl.

In one embodiment, X₄ is selected from ethynyl, propynyl (e.g.,1-propynyl or 2-propynyl), butynyl (e.g., 1-butynyl, 2-butynyl, or3-butynyl), pentynyl (e.g., 1-pentynyl, 2-pentynyl, 3-pentynyl, or4-pentynyl), and hexynyl (e.g., 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, or 5-hexynyl). In one embodiment, X₄ is 1-propynyl or2-propynyl.

In one embodiment, X₅ is phenyl-(CX₈X₈), phenyl-(CX₈X₈)₂, orphenyl-(CX₈X₈)₃, wherein the phenyl is optionally substituted with oneor more substituents independently selected from deuterium, F, SF₅,C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from C₁-C₄ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with oneor more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F), C₁-C₄ alkoxy(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy), and C₁-C₄ alkoxy substituted with one or more F (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, eachof which is substituted with one or more F).

In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, C₁-C₄ alkyl substituted withone or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F), and C₁-C₄alkoxy substituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, SF₅, CF₃, CHF₂,CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂,and OCH₂CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, the phenyl is substituted with one or moregroups independently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, CF₃, and OCF₃.

In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, thephenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, and CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from Fand CF₃.

In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkoxy substitutedwith one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment,the phenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F and OCF₃.

In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from C₁-C₄ alkyl (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and C₁-C₄ alkoxy(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy). In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from CH₃, CH₂CH₃, OCH₃, and OCH₂CH₃.In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the phenyl is substituted with one or more CH₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from OCH₃ and OCH₂CH₃. In one embodiment, thephenyl is substituted with one or more OCH₃.

In one embodiment, the substituent is attached at the para-position onthe phenyl ring. In one embodiment, the substituent(s) are attached atthe meta-position(s) on the phenyl ring. In one embodiment, thesubstituent(s) are attached at the ortho-position(s) on the phenyl ring.

In one embodiment, X₅ is 2-fluoro-benzyl. In one embodiment, X₅ is3-fluoro-benzyl. In one embodiment, X₅ is 4-fluoro-benzyl. In oneembodiment, X₅ is 2-fluoro-benzyl. In one embodiment, X₅ is3-fluoro-benzyl. In one embodiment, X₅ is 2-trifluoromethyl-benzyl. Inone embodiment, X₅ is 3-trifluoromethyl-benzyl. In one embodiment, X₅ is4-trifluoromethyl-benzyl. In one embodiment, X₅ is2-trifluoromethoxy-benzyl. In one embodiment, X₅ is3-trifluoromethoxy-benzyl. In one embodiment, X₅ is4-trifluoromethoxy-benzyl.

In one embodiment, each X₈ is H. In one embodiment, at least one X₈ isdeuterium, F, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl), or C₁-C₄ alkyl substituted with one or more F(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, eachof which is substituted with one or more F). In one embodiment, at leastone X₈ is deuterium. In one embodiment, at least one X₈ is F, C₁-C₄alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), or C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F). In one embodiment, at least one X₈ isC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl) or C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F). In one embodiment, at least one X₈ is For C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F). In one embodiment, at least one X₈ isC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl). In one embodiment, at least one X₈ is C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F).In one embodiment, at least one X₈ is F.

In one embodiment, X₄ and X₈, together with the nitrogen atom to whichthey are attached, form a 5- to 7-membered heterocyclic ring comprising1 or 2 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrothiapyranyl, dioxanyl, morpholinyl,oxazinanyl, thiazinanyl, or oxathianyl). In one embodiment, X₄ and X₅,together with the nitrogen atom to which they are attached, form a 5- to7-membered heterocyclic ring comprising 1 heteroatom selected from N, O,and S. In one embodiment, X₄ and X₅, together with the nitrogen atom towhich they are attached, form a 5- or 6-membered heterocyclic ringcomprising 1 heteroatom selected from N, O, and S. In one embodiment, X₄and X₅, together with the nitrogen atom to which they are attached, forma 5- or 6-membered heterocyclic ring comprising 1 heteroatom selectedfrom N and O. In one embodiment, X₄ and X₅, together with the nitrogenatom to which they are attached, form a pyrrolidinyl or piperidinylring.

In one embodiment, X₄ and X₅, together with the nitrogen atom to whichthey are attached, form a 5- to 7-membered heterocyclic ring optionallysubstituted with one or more substituents independently selected fromdeuterium, F, SF₅, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, eachof which is substituted with one or more F), C₁-C₄ alkoxy (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), andC₁-C₄ alkoxy substituted with one or more F (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which issubstituted with one or more F). In one embodiment, the heterocyclicring is substituted with one or more substituents independently selectedfrom F, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each ofwhich is substituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄alkoxy substituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the heterocyclic ring issubstituted with one or more substituents independently selected fromC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the heterocyclic ring issubstituted with one or more substituents independently selected from F,C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), and C₁-C₄ alkoxy substituted with one or more F (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, eachof which is substituted with one or more F). In one embodiment, theheterocyclic ring is substituted with one or more substituentsindependently selected from F, SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂,CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In oneembodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F, CF₃, CHF₂, CH₂F, CH₂CF₃,CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F.In one embodiment, the heterocyclic ring is substituted with one or moregroups independently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one embodiment, the heterocyclic ring is substituted with oneor more substituents independently selected from F, CF₃, and OCF₃. Inone embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F).In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the heterocyclic ringis substituted with one or more substituents independently selected fromF, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, theheterocyclic ring is substituted with one or more groups independentlyselected from F, CF₃, CHF₂, and CH₂F. In one embodiment, theheterocyclic ring is substituted with one or more substituentsindependently selected from F and CF₃. In one embodiment, theheterocyclic ring is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the heterocyclicring is substituted with one or more substituents independently selectedfrom F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In oneembodiment, the heterocyclic ring is substituted with one or more groupsindependently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F and OCF₃. In one embodiment,the heterocyclic ring is substituted with one or more substituentsindependently selected from C₁-C₄ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl) and C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy). In oneembodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from CH₃, CH₂CH₃, OCH₃, and OCH₂CH₃.In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the heterocyclic ring is substituted with one or more CH₃.In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from OCH₃ and OCH₂CH₃. In oneembodiment, the heterocyclic ring is substituted with one or more OCH₃.

In one embodiment, X₄ and X₅, together with the nitrogen atom to whichthey are attached, form a 5- to 7-membered heterocyclic ring substitutedwith two or more substituents, wherein two substituents attached toadjacent carbon atoms on the heterocyclic ring, together with the carbonatoms to which they are attached, form a phenyl optionally substitutedwith one or more substituents independently selected from deuterium, F,SF₅, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from C₁-C₄ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with oneor more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F), C₁-C₄ alkoxy(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy), and C₁-C₄ alkoxy substituted with one or more F (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, eachof which is substituted with one or more F). In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F, C₁-C₄ alkyl substituted with one or more F (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each ofwhich is substituted with one or more F), and C₁-C₄ alkoxy substitutedwith one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, CF₃, CHF₂, CH₂F, CH₂CF₃,CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F.In one embodiment, the phenyl is substituted with one or more groupsindependently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, CF₃, and OCF₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkyl substituted with one ormore F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂,and CH₂CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more groups independently selected from F, CF₃,CHF₂, and CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F and CF₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from F, OCF₃,OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, thephenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F and OCF₃. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from CH₃, CH₂CH₃,OCH₃, and OCH₂CH₃. In one embodiment, the phenyl is substituted with oneor more substituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the phenyl is substituted with one or more CH₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from OCH₃ and OCH₂CH₃. In one embodiment, thephenyl is substituted with one or more OCH₃.

In one embodiment, X₄ and X₅, together with the nitrogen atom to whichthey are attached, form a heterocyclic ring selected from

wherein the nitrogen atom is the nitrogen atom bonded to X₄ and X₅. Inone embodiment, X₄ and X₅, together with the nitrogen atom to which theyare attached, form

wherein the nitrogen atom is the nitrogen atom bonded to X₄ and X₅.

In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment,m is 3.

Any of the substituent groups described above for any of X₁, X₄, X₅, X₈,X₉, and m can be combined with any of the substituent groups describedabove for one or more of the remainder of X₁, X₄, X₅, X₈, X₉, and m.

(1a) In one embodiment, X₄ is C₁-C₄ alkyl, and X₅ is phenyl-(CX₈X₈)_(m).In one embodiment, the phenyl is optionally substituted with one or moresubstituents independently selected from deuterium, F, SF₅, C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with oneor more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F), C₁-C₄ alkoxy(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy), and C₁-C₄ alkoxy substituted with one or more F (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, eachof which is substituted with one or more F). In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each ofwhich is substituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄alkoxy substituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, C₁-C₄ alkylsubstituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl, each of which is substituted with one ormore F), and C₁-C₄ alkoxy substituted with one or more F (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of whichis substituted with one or more F). In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl is substitutedwith one or more groups independently selected from F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from F, CF₃, andOCF₃. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, thephenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, and CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from Fand CF₃. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkoxy substitutedwith one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment,the phenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F and OCF₃. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from CH₃, CH₂CH₃,OCH₃, and OCH₂CH₃. In one embodiment, the phenyl is substituted with oneor more substituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the phenyl is substituted with one or more CH₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from OCH₃ and OCH₂CH₃. In one embodiment, thephenyl is substituted with one or more OCH₃.

(1b) In one embodiment, X₄ is C₂-C₆ alkenyl, and X₅ isphenyl-(CX₈X₈)_(m). In one embodiment, the phenyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, SF₅, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, eachof which is substituted with one or more F), C₁-C₄ alkoxy (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), andC₁-C₄ alkoxy substituted with one or more F (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which issubstituted with one or more F). In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from C₁-C₄ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, C₁-C₄ alkyl substituted with one or moreF (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,each of which is substituted with one or more F), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, SF₅, CF₃, CHF₂,CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂,and OCH₂CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, the phenyl is substituted with one or moregroups independently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, CF₃, and OCF₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkyl substituted with one ormore F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂,and CH₂CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more groups independently selected from F, CF₃,CHF₂, and CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F and CF₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from F, OCF₃,OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, thephenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F and OCF₃. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from CH₃, CH₂CH₃,OCH₃, and OCH₂CH₃. In one embodiment, the phenyl is substituted with oneor more substituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the phenyl is substituted with one or more CH₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from OCH₃ and OCH₂CH₃. In one embodiment, thephenyl is substituted with one or more OCH₃.

(1c) In one embodiment, X₄ is C₂-C₆ alkynyl, and X₅ isphenyl-(CX₈X₈)_(m). In one embodiment, the phenyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, SF₅, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, eachof which is substituted with one or more F), C₁-C₄ alkoxy (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), andC₁-C₄ alkoxy substituted with one or more F (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which issubstituted with one or more F). In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from C₁-C₄ alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, C₁-C₄ alkyl substituted with one or moreF (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,each of which is substituted with one or more F), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, SF₅, CF₃, CHF₂,CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂,and OCH₂CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, the phenyl is substituted with one or moregroups independently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, CF₃, and OCF₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkyl substituted with one ormore F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂,and CH₂CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more groups independently selected from F, CF₃,CHF₂, and CH₂F. In one embodiment, the phenyl is substituted with one ormore substituents independently selected from F and CF₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from F, OCF₃,OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, thephenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F and OCF₃. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from CH₃, CH₂CH₃,OCH₃, and OCH₂CH₃. In one embodiment, the phenyl is substituted with oneor more substituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the phenyl is substituted with one or more CH₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from OCH₃ and OCH₂CH₃. In one embodiment, thephenyl is substituted with one or more OCH₃.

(1d) In one embodiment, X₄ and X₅, together with the nitrogen atom towhich they are attached, form a 5- to 7-membered heterocyclic ringcomprising 1 to 2 heteroatoms selected from N, O, and S, optionallysubstituted with one or more substituents independently selected fromdeuterium, F, SF₅, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, eachof which is substituted with one or more F), C₁-C₄ alkoxy (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), andC₁-C₄ alkoxy substituted with one or more F (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which issubstituted with one or more F). In one embodiment, the heterocyclicring is substituted with one or more substituents independently selectedfrom F, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each ofwhich is substituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄alkoxy substituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the heterocyclic ring issubstituted with one or more substituents independently selected fromC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the heterocyclic ring issubstituted with one or more substituents independently selected from F,C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted withone or more F), and C₁-C₄ alkoxy substituted with one or more F (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, eachof which is substituted with one or more F). In one embodiment, theheterocyclic ring is substituted with one or more substituentsindependently selected from F, SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂,CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In oneembodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F, CF₃, CHF₂, CH₂F, CH₂CF₃,CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F.In one embodiment, the heterocyclic ring is substituted with one or moregroups independently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, andOCH₂F. In one embodiment, the heterocyclic ring is substituted with oneor more substituents independently selected from F, CF₃, and OCF₃. Inone embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F).In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the heterocyclic ringis substituted with one or more substituents independently selected fromF, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, theheterocyclic ring is substituted with one or more groups independentlyselected from F, CF₃, CHF₂, and CH₂F. In one embodiment, theheterocyclic ring is substituted with one or more substituentsindependently selected from F and CF₃. In one embodiment, theheterocyclic ring is substituted with one or more substituentsindependently selected from F and C₁-C₄ alkoxy substituted with one ormore F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the heterocyclicring is substituted with one or more substituents independently selectedfrom F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In oneembodiment, the heterocyclic ring is substituted with one or more groupsindependently selected from F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F.In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from F and OCF₃.

In one embodiment, the heterocyclic ring is substituted with one or moresubstituents independently selected from C₁-C₄ alkyl (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and C₁-C₄ alkoxy(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy). In one embodiment, the heterocyclic ring is substituted withone or more substituents independently selected from CH₃, CH₂CH₃, OCH₃,and OCH₂CH₃. In one embodiment, the heterocyclic ring is substitutedwith one or more substituents independently selected from CH₃ andCH₂CH₃. In one embodiment, the heterocyclic ring is substituted with oneor more CH₃. In one embodiment, the heterocyclic ring is substitutedwith one or more substituents independently selected from OCH₃ andOCH₂CH₃. In one embodiment, the heterocyclic ring is substituted withone or more OCH₃.

(1e) In one embodiment, X₄ and X₅, together with the nitrogen atom towhich they are attached, form a 5- to 7-membered heterocyclic ringsubstituted with two or more substituents, wherein two substituentsattached to adjacent carbon atoms on the heterocyclic ring, togetherwith the carbon atoms to which they are attached, form a phenyloptionally substituted with one or more substituents independentlyselected from deuterium, F, SF₅, C₁-C₄ alkyl (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F),C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy), and C₁-C₄ alkoxy substituted with one or more F(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from F, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl), C₁-C₄ alkyl substituted with oneor more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F), C₁-C₄ alkoxy(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy), and C₁-C₄ alkoxy substituted with one or more F (e.g.,methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, eachof which is substituted with one or more F). In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each ofwhich is substituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄alkoxy substituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, the phenyl is substituted withone or more substituents independently selected from F, C₁-C₄ alkylsubstituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl, each of which is substituted with one ormore F), and C₁-C₄ alkoxy substituted with one or more F (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of whichis substituted with one or more F). In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,SF₅, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl is substitutedwith one or more groups independently selected from F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from F, CF₃, andOCF₃. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkyl substitutedwith one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, thephenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, and CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from Fand CF₃. In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F and C₁-C₄ alkoxy substitutedwith one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy, each of which is substituted with one or more F).In one embodiment, the phenyl is substituted with one or moresubstituents independently selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, the phenyl issubstituted with one or more substituents independently selected from F,OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment,the phenyl is substituted with one or more groups independently selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, thephenyl is substituted with one or more substituents independentlyselected from F and OCF₃. In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, the phenyl is substitutedwith one or more substituents independently selected from CH₃, CH₂CH₃,OCH₃, and OCH₂CH₃. In one embodiment, the phenyl is substituted with oneor more substituents independently selected from CH₃ and CH₂CH₃. In oneembodiment, the phenyl is substituted with one or more CH₃. In oneembodiment, the phenyl is substituted with one or more substituentsindependently selected from OCH₃ and OCH₂CH₃. In one embodiment, thephenyl is substituted with one or more OCH₃.

(2a) In one embodiment, m is 1.

(2b) In one embodiment, m is 2.

(2c) In one embodiment, m is 3.

(3a) In one embodiment, each X₈ is H.

(3b) In one embodiment, at least one X₈ is deuterium.

(3c) In one embodiment, at least one X₈ is C₁-C₄ alkyl, C₁-C₄ alkylsubstituted with one or more F, or F.

(4a) In one embodiment, X₁ is methyl, and X₉ is methyl.

(4b) In one embodiment, X₁ is methyl, and X₉ is ethyl.

(4c) In one embodiment, X₁ is ethyl, and X₉ is ethyl.

(A1a) In one embodiment, X₄ and X₅ are each as defined in (1a), and m isas defined in any one of (2a)-(2c). In a further embodiment, m is asdefined in (2a).

(A1b) In one embodiment, X₄ and X₅ are each as defined in (1b), and m isas defined in any one of (2a)-(2c). In a further embodiment, m is asdefined in (2a).

(A1c) In one embodiment, X₄ and X₅ are each as defined in (1c), and m isas defined in any one of (2a)-(2c). In a further embodiment, m is asdefined in (2a).

(A1d) In one embodiment, X₄ and X₅ are each as defined in (1d), and m isas defined in any one of (2a)-(2c). In a further embodiment, m is asdefined in (2a).

(A1e) In one embodiment, X₄ and X₅ are each as defined in (1e), and m isas defined in any one of (2a)-(2c). In a further embodiment, m is asdefined in (2a).

(B1a) In one embodiment, X₄, X₅, and m are each as defined in any one of(A1a)-(A1e), and X₈ is as defined in (3a).

(B1b) In one embodiment, X₄, X₅, and m are each as defined in any one of(A1a)-(A1e), and X₈ is as defined in (3b).

(B1c) In one embodiment, X₄, X₅, and m are each as defined in any one of(A1a)-(A1e), and X₈ is as defined in (3c).

(C1a) In one embodiment, X₄, X₅, X₈, and m are each as defined in anyone of (B1a)-(B1c), and X₁ and X₉ are as defined in (4a).

(C1b) In one embodiment, X₄, X₅, X₈, and m are each as defined in anyone of (B1a)-(B1c), and X₁ and X₉ are as defined in (4b).

(C1c) In one embodiment, X₄, X₅, X₈, and m are each as defined in anyone of (B1a)-(B1c), and X₁ and X₉ are as defined in (4c).

In one embodiment, the compound of formula A is of formula IIa or IIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X₄ and m are each as defined above in formula A;

t1 is 1, 2, 3, 4, or 5; and

each Z₁ is independently deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkylsubstituted with one or more F, C₁-C₄ alkoxy, or C₁-C₄ alkoxysubstituted with one or more F.

For a compound of formula IIa or IIb, t1 and Z₁ can each be, whereapplicable, selected from the groups described herein below, and anygroup described herein for any of t1 and Z₁ can be combined, whereapplicable, with any group described herein for the remainder of t1 andZ₁.

In one embodiment, t1 is 1, 2, or 3. In one embodiment, t1 is 1 or 2. Inone embodiment, t1 is 1. In one embodiment, t1 is 2. In one embodiment,t1 is 3. In one embodiment, t1 is 4. In one embodiment, t1 is 5.

In one embodiment, at least one Z₁ is selected from deuterium, F, SF₅,C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₁ is selected fromF, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₁ is selected fromC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₁ is selected fromF, C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), and C₁-C₄ alkoxy substituted with oneor more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy,or t-butoxy, each of which is substituted with one or more F). In oneembodiment, at least one Z₁ is selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, at least one Z₁ is selected from F, CF₃,CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, at least one Z₁ is selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, atleast one Z₁ is selected from F, CF₃, and OCF₃. In one embodiment, atleast one Z₁ is selected from F and C₁-C₄ alkyl substituted with one ormore F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F). In oneembodiment, at least one Z₁ is selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, at least one Z₁ isselected from F, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In oneembodiment, at least one Z₁ is selected from F, CF₃, CHF₂, and CH₂F. Inone embodiment, the phenyl is substituted with one or more substituentsindependently selected from F and CF₃. In one embodiment, at least oneZ₁ is selected from F and C₁-C₄ alkoxy substituted with one or more F(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, at least one Z₁ is selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, at least one Z₁ isselected from F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. Inone embodiment, at least one Z₁ is selected from F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F. In one embodiment, at least one Z₁ is selectedfrom F and OCF₃. In one embodiment, at least one Z₁ is F. In oneembodiment, at least one Z₁ is CF₃. In one embodiment, at least one Z₁is OCF₃. In one embodiment, at least one Z₁ is selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, at least one Z₁ is selectedfrom CH₃, CH₂CH₃, OCH₃, and OCH₂CH₃. In one embodiment, at least one Z₁is selected from CH₃ and CH₂CH₃. In one embodiment, at least one Z₁ isCH₃. In one embodiment, at least one Z₁ is selected from OCH₃ andOCH₂CH₃. In one embodiment, at least one Z₁ is OCH₃.

For a compound of formula IIa or IIb, X₄ and m can each be selected fromany of the substituents described above in formula A, and any of thesubstituents described above for any of X₄ and m can be combined withany of the substituents described above for one or more of the remainderof X₄ and m, and can further be combined with any of the substituentsdescribed for any of t1 and Z₁.

In one embodiment, t1 is 1, and Z₁ is F, CF₃, or OCF₃. In oneembodiment, t1 is 1, and Z₁ is F. In one embodiment, t1 is 1, and Z₁ isCF₃. In one embodiment, t1 is 1, and Z₁ is OCF₃.

In one embodiment, t1 is 1, Z₁ is F, CF₃, or OCF₃, and m is 1. In oneembodiment, t1 is 1, Z₁ is F, and m is 1. In one embodiment, t1 is 1, Z₁is CF₃, and m is 1. In one embodiment, t1 is 1, Z₁ is OCF₃, and m is 1.

In one embodiment, t1 is 1, Z₁ is F, CF₃, or OCF₃, m is 1, and X₄ is H.In one embodiment, t1 is 1, Z₁ is F, m is 1, and X₄ is H. In oneembodiment, t1 is 1, Z₁ is CF₃, m is 1, and X₄ is H. In one embodiment,t1 is 1, Z₁ is OCF₃, m is 1, and X₄ is H.

In one embodiment, t1 is 1, and Z₁ is CH₃ or OCH₃. In one embodiment, t1is 1, and Z₁ is CH₃. In one embodiment, t1 is 1, and Z₁ is OCH₃.

In one embodiment, t1 is 1, and Z₁ is CH₃ or OCH₃, and m is 1. In oneembodiment, t1 is 1, and Z₁ is CH₃, and m is 1. In one embodiment, t1 is1, and Z₁ is OCH₃, and m is 1.

In one embodiment, t1 is 1, and Z₁ is CH₃ or OCH₃, m is 1, and X₄ is H.In one embodiment, t1 is 1, and Z₁ is CH₃, m is 1, and X₄ is H. In oneembodiment, t1 is 1, and Z₁ is OCH₃, m is 1, and X₄ is H.

In one embodiment, the compound of formula A is of formula IIIa or IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

q is 1, 2, or 3;

t2 is 1, 2, 3, or 4; and

each Z₂ is independently deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkylsubstituted with one or more F, C₁-C₄ alkoxy, or C₁-C₄ alkoxysubstituted with one or more F.

For a compound of formula IIIa or IIIb, q, t2 and Z₂ can each be, whereapplicable, selected from the groups described herein below, and anygroup described herein for any of q, t2 and Z₂ can be combined, whereapplicable, with any group described herein for the remainder of q, t2and Z₂.

In one embodiment, q is 1. In one embodiment, q is 2. In one embodiment,q is 3.

In one embodiment, t2 is 1. In one embodiment, t2 is 2. In oneembodiment, t2 is 3. In one embodiment, t2 is 4.

In one embodiment, at least one Z₂ is selected from deuterium, F, SF₅,C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₂ is selected fromF, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₂ is selected fromC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₂ is selected fromF, C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), and C₁-C₄ alkoxy substituted with oneor more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy,or t-butoxy, each of which is substituted with one or more F). In oneembodiment, at least one Z₂ is selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, at least one Z₂ is selected from F, CF₃,CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, at least one Z₂ is selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, atleast one Z₂ is selected from F, CF₃, and OCF₃. In one embodiment, atleast one Z₂ is selected from F and C₁-C₄ alkyl substituted with one ormore F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F). In oneembodiment, at least one Z₂ is selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, at least one Z₂ isselected from F, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In oneembodiment, at least one Z₂ is selected from F, CF₃, CHF₂, and CH₂F. Inone embodiment, the phenyl is substituted with one or more substituentsindependently selected from F and CF₃. In one embodiment, at least oneZ₂ is selected from F and C₁-C₄ alkoxy substituted with one or more F(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, at least one Z₂ is selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, at least one Z₂ isselected from F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. Inone embodiment, at least one Z₂ is selected from F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F. In one embodiment, at least one Z₂ is selectedfrom F and OCF₃. In one embodiment, at least one Z₂ is F. In oneembodiment, at least one Z₂ is CF₃. In one embodiment, at least one Z₂is OCF₃. In one embodiment, at least one Z₂ is selected from C₁-C₄ alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) andC₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy, or t-butoxy). In one embodiment, at least one Z₂ is selectedfrom CH₃, CH₂CH₃, OCH₃, and OCH₂CH₃. In one embodiment, at least one Z₂is selected from CH₃ and CH₂CH₃. In one embodiment, at least one Z₂ isCH₃. In one embodiment, at least one Z₂ is selected from OCH₃ andOCH₂CH₃. In one embodiment, at least one Z₂ is OCH₃.

In one embodiment, the compound of formula A is of formula IVa or IVb:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

r is 1, 2, or 3;

t3 is 1, 2, 3, or 4; and

each Z₃ is independently deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkylsubstituted with one or more F, C₁-C₄ alkoxy, or C₁-C₄ alkoxysubstituted with one or more F.

For a compound of formula IVa or IVb, r, t3 and Z₃ can each be, whereapplicable, selected from the groups described herein below, and anygroup described herein for any of q, t2 and Z₃ can be combined, whereapplicable, with any group described herein for the remainder of q, t2and Z₃.

In one embodiment, r is 1. In one embodiment, r is 2. In one embodiment,r is 3.

In one embodiment, t3 is 1. In one embodiment, t3 is 2. In oneembodiment, t3 is 3. In one embodiment, t3 is 4.

In one embodiment, at least one Z₃ is selected from deuterium, F, SF₅,C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₃ is selected fromF, C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,or t-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₃ is selected fromC₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl), C₁-C₄ alkyl substituted with one or more F (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and C₁-C₄ alkoxysubstituted with one or more F (e.g., methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is substitutedwith one or more F). In one embodiment, at least one Z₃ is selected fromF, C₁-C₄ alkyl substituted with one or more F (e.g., methyl, ethyl,propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which issubstituted with one or more F), and C₁-C₄ alkoxy substituted with oneor more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy,or t-butoxy, each of which is substituted with one or more F). In oneembodiment, at least one Z₃ is selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, andOCH₂CH₂F. In one embodiment, at least one Z₃ is selected from F, CF₃,CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, at least one Z₃ is selectedfrom F, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, and OCH₂F. In one embodiment, atleast one Z₃ is selected from F, CF₃, and OCF₃. In one embodiment, atleast one Z₃ is selected from F and C₁-C₄ alkyl substituted with one ormore F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, ort-butyl, each of which is substituted with one or more F). In oneembodiment, at least one Z₃ is selected from F, SF₅, CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In one embodiment, at least one Z₃ isselected from F, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, and CH₂CH₂F. In oneembodiment, at least one Z₃ is selected from F, CF₃, CHF₂, and CH₂F. Inone embodiment, the phenyl is substituted with one or more substituentsindependently selected from F and CF₃. In one embodiment, at least oneZ₃ is selected from F and C₁-C₄ alkoxy substituted with one or more F(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, ort-butoxy, each of which is substituted with one or more F). In oneembodiment, at least one Z₃ is selected from F, SF₅, OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. In one embodiment, at least one Z₃ isselected from F, OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCH₂CHF₂, and OCH₂CH₂F. Inone embodiment, at least one Z₃ is selected from F, CF₃, CHF₂, CH₂F,OCF₃, OCHF₂, and OCH₂F. In one embodiment, at least one Z₃ is selectedfrom F and OCF₃. In one embodiment, at least one Z₃ is F. In oneembodiment, at least one Z₃ is CH₃. In one embodiment, at least one Z₃is CF₃. In one embodiment, at least one Z₃ is OCH₃. In one embodiment,at least one Z₃ is OCF₃. In one embodiment, at least one Z₃ is selectedfrom C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl,or t-butyl) and C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, or t-butoxy). In one embodiment, at least one Z₃ isselected from CH₃, CH₂CH₃, OCH₃, and OCH₂CH₃. In one embodiment, atleast one Z₃ is selected from CH₃ and CH₂CH₃. In one embodiment, atleast one Z₃ is CH₃. In one embodiment, at least one Z₃ is selected fromOCH₃ and OCH₂CH₃. In one embodiment, at least one Z₃ is OCH₃.

In one embodiment, a compound of the present application is selectedfrom the compounds in Table 1.

TABLE 1 Compound No. Structure 1

2

3

4

5

6

In one embodiment, a compound of the application is a pharmaceuticallyacceptable salt. In one embodiment, a compound of the application is asolvate. In one embodiment, a compound of the application is a hydrate.

A “selective KCNQ2/3 channel modulator” or “selective KCNQ2/3 channelopener” can be identified, for example, by comparing the ability of acompound to modulate KCNQ2/3 potassium channel (e.g., open KCNQ2/3potassium channel) to its ability to modulate the other potassiumchannels (e.g., open other potassium channels). For example, a substancemay be assayed for its ability to modulate KCNQ2/3 potassium channel,KCNQ3/5 potassium channel, KCNQ4 potassium channel, and/or otherpotassium channels (e.g., open KCNQ2/3 potassium channel, KCNQ3/5potassium channel, KCNQ4 potassium channel, and/or other potassiumchannels). In some embodiments, the selectivity can be identified bymeasuring the EC₅₀ or IC₅₀ of the compounds.

In some embodiments, one or more of the compounds of the presentapplication modulate KCNQ2/3 potassium channel more selectively overother potassium channels. In some embodiments, one or more of thecompounds of the present application are about 10%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,or about 99% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel). In some embodiments, one or more of the compounds ofthe present application are about 10%, about 20%, about 30%, about 40%,or about 50% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel). In some embodiments, one or more of the compounds ofthe present application are about 20%, about 30%, about 40%, about 50%,or about 60% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel). In some embodiments, one or more of the compounds ofthe present application are about 30%, about 40%, about 50%, about 60%,or about 70% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel). In some embodiments, one or more of the compounds ofthe present application are about 40%, about 50%, about 60%, about 70%,or about 80% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel). In some embodiments, one or more of the compounds ofthe present application are about 50%, about 60%, about 70%, about 80%,or about 90% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel). In some embodiments, one or more of the compounds ofthe present application are about 60%, about 70%, about 80%, about 90%,or about 99% more selective at modulating KCNQ2/3 potassium channel(e.g., opening KCNQ2/3 potassium channel) more selectively over otherpotassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4potassium channel).

In some embodiments, one or more of the compounds of the presentapplication are between about 10% and about 99% more selective moreselective at modulating KCNQ2/3 potassium channel (e.g., open KCNQ2/3potassium channel) more selectively over other potassium channels (e.g.,KCNQ3/5 potassium channel and/or KCNQ4 potassium channel). In someembodiments, one or more of the compounds of the present application arebetween about 10% and about 30% more selective more selective atmodulating KCNQ2/3 potassium channel (e.g., open KCNQ2/3 potassiumchannel) more selectively over other potassium channels (e.g., KCNQ3/5potassium channel and/or KCNQ4 potassium channel). In some embodiments,one or more of the compounds of the present application are betweenabout 20% and about 40% more selective more selective at modulatingKCNQ2/3 potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel). In some embodiments, one ormore of the compounds of the present application are between about 30%and about 50% more selective more selective at modulating KCNQ2/3potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel). In some embodiments, one ormore of the compounds of the present application are between about 40%and about 60% more selective more selective at modulating KCNQ2/3potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel). In some embodiments, one ormore of the compounds of the present application are between about 50%and about 70% more selective more selective at modulating KCNQ2/3potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel). In some embodiments, one ormore of the compounds of the present application are between about 60%and about 80% more selective more selective at modulating KCNQ2/3potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel). In some embodiments, one ormore of the compounds of the present application are between about 70%and about 90% more selective more selective at modulating KCNQ2/3potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel). In some embodiments, one ormore of the compounds of the present application are between about 80%and about 99% more selective more selective at modulating KCNQ2/3potassium channel (e.g., open KCNQ2/3 potassium channel) moreselectively over other potassium channels (e.g., KCNQ3/5 potassiumchannel and/or KCNQ4 potassium channel).

As used herein, “selective”, “selective KCNQ2/3 channel modulator”,“selective KCNQ2/3 channel opener”, or “selective KCNQ2/3 compound”refers to a compound, e.g., a compound of the application, thateffectively modulates KCNQ2/3 potassium channel (e.g., opens KCNQ2/3potassium channel) to a greater extent than other potassium channels(e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassium channel).

In some embodiments, the compounds of the application are KCNQ2/3channel modulators that modulates KCNQ2/3 potassium channel (e.g., opensKCNQ2/3 potassium channel) with at least 2-fold, 3-fold, 5-fold,10-fold, 25-fold, 50-fold or 100-fold selectivity over other potassiumchannels (e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassiumchannel).

The present application relates to pharmaceutical compositionscomprising one of the compounds of the application as an activeingredient. In one embodiment, the application provides a pharmaceuticalcomposition comprising at least one compound disclosed herein (e.g., acompound of formula A, Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, or IVb), or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable carrier or excipient. In one embodiment, theapplication provides a pharmaceutical composition comprising at leastone compound of Table 1, or a pharmaceutically acceptable salt orsolvate thereof, and one or more pharmaceutically acceptable carrier orexcipient.

The present application relates to a method of synthesizing a compoundof the application or a pharmaceutically acceptable salt or solvatethereof. A compound of the application can be synthesized using avariety of methods known in the art, such as those described in U.S.Pat. No. 8,916,133, the contents of which are incorporated by referencein their entirety. The schemes and description below depict generalroutes for the preparation of a compound of the application. Forexample, compounds of the present application can be synthesized byfollowing the steps outlined in Schemes 1-2 which comprise differentsequences of assembling intermediates 1a-1e and 2a-2f. Startingmaterials are either commercially available or made by known proceduresin the reported literature or as illustrated.

The general way of preparing representative compounds of the presentapplication using intermediates 1a-1e is outlined in Scheme 1.Nucleophilic addition of 1a to fluoride 1b in the presence of a base(e.g., triethylamine (Et₃N)) in a solvent (e.g., dimethylsulfoxide(DMSO)) and optionally at an elevated temperature provides intermediate1c. Methylation of 1c with a base (e.g., sodium hydride (NaH)) and analkyltriphenylphosphonium salt (e.g., methyltriphenylphosphonium bromide(MePPh₃Br)) in a solvent (e.g., tetrahydrofuran (THF)) and optionally atan elevated temperature provides intermediate 1d. Reduction of 1d usinga metal catalyst (e.g., Zinc (Zn)) and ammonium chloride (NH₄Cl) in asolvent (e.g., methanol (MeOH) and water (H₂O)) and optionally at anelevated temperature provides intermediate 1e. Acetylation of 1e withtert-butylacetyl chloride in the presence of a base (e.g.,diisopropylethylamine (DIPEA)) in a solvent (e.g., dichloromethane(DCM)) and optionally at an elevated temperature provides a compound offormula Ia.

The general way of preparing representative compounds of the presentapplication using intermediates 2a-2f is outlined in Scheme 2.Nucleophilic addition of 2a to fluoride 2b in the presence of a base(e.g., triethylamine (Et₃N)) in a solvent (e.g., dimethylsulfoxide(DMSO)) and optionally at an elevated temperature provides intermediate2c. Methylation of 2c with a base (e.g., sodium hydride (NaH)) and analkyltriphenylphosphonium salt (e.g., methyltriphenylphosphonium bromide(MePPh₃Br)) in a solvent (e.g., tetrahydrofuran (THF)) and optionally atan elevated temperature provides intermediate 2d. Reduction of 2d usinga metal catalyst (e.g., Zinc (Zn)) and ammonium chloride (NH₄Cl) in asolvent (e.g., methanol (MeOH) and water (H₂O)) and optionally at anelevated temperature provides intermediate 2e. Acetylation of 2e withtert-butylacetyl chloride in the presence of a base (e.g.,diisopropylethylamine (DIPEA)) in a solvent (e.g., dichloromethane(DCM)) and optionally at an elevated temperature provides intermediate2f. Deprotection of 2f in the presence of an acid (e.g., hydrochloricacid (HCl)) in a solvent (e.g., dichloromethane (DCM) and water (H₂O))and optionally at an elevated temperature provides a compound of formulaIaa.

The present application also comprehends deuterium labeled compounds,wherein one or more hydrogen atoms is replaced by a deuterium atomhaving an abundance of deuterium at that position that is substantiallygreater than the natural abundance of deuterium, which is 0.015%.

Deuterium labeled compounds can be prepared by using any of a variety ofart-recognized techniques. For example, deuterium labeled compounds ofany of the formulae described herein and compounds listed in Table 1 ofthis application can be prepared.

In one aspect, a deuterium labeled compound of the application is apharmaceutically acceptable salt. In one aspect, a deuterium labeledcompound of the application is a solvate. In one aspect, a deuteriumlabeled compound of the application is a hydrate.

The present application relates to pharmaceutical compositionscomprising one of the deuterium labeled compounds of the application asan active ingredient. In one aspect, the application provides apharmaceutical composition comprising at least one deuterium labeledcompound of any of the formulae described herein or a pharmaceuticallyacceptable salt or solvate thereof and one or more pharmaceuticallyacceptable carrier or excipient.

The present application relates to a method of synthesizing a deuteriumlabeled compound of the application or a pharmaceutically acceptablesalt or solvate thereof. The deuterium labeled compounds of theapplication can be prepared using any of a variety of art-recognizedtechniques, such as those described in U.S. Pat. No. 8,916,133, thecontents of which are incorporated by reference in their entirety. Forexample, a deuterium labeled compound can be prepared by starting withdeuterium labeled Compound 1 and/or substituting a readily availabledeuterium labeled reagent for a non-deuterium labeled reagent.

The scheme and description below depicts a general route for theincorporation of deuterium label to produce a deuterium labeled compoundof the application.

Scheme 1A outlines a preparation for a deuterium labeled compound of theapplication. The preparation begins with Compound A (from Scheme 1Adescribed herein). In Step 1, the nitro group of Compound A is reducedand then the deuterium label is introduced via formation of a carbamatecontaining one or more deuterium. For example, the nitro group ofCompound A can be reduced using zinc powder and ammonium chloride inmethanol and the carbamate can be formed using ethyl-d₅ chloroformate toprovide a deuterium labeled compound.

In some embodiments, temporary protecting groups may be used to preventother reactive functionality, such as amines, thiols, alcohols, phenols,and carboxylic acids, from participating or interfering in thefluorination reaction. Representative amine protecting groups include,for example, tert-butoxycarbonyl and trityl (removed under acidconditions), Fmoc (removed by the use of secondary amines such aspiperidine), and benzyloxycarbonyl (removed by strong acid or bycatalytic hydrogenolysis). The trityl group may also be used for theprotection of thiols, phenols, and alcohols. In certain embodiments thecarboxylic acid protecting groups include, for example, tert-butyl ester(removed by mild acid), benzyl ester (usually removed by catalytichydrogenolysis), and alkyl esters such as methyl or ethyl (usuallyremoved by mild base). All protecting groups may be removed at theconclusion of the synthesis using the conditions described above for theindividual protecting groups, and the final product may be purified bytechniques which would be readily apparent to one of ordinary skill inthe art, in combination with the teachings described herein.

Biological Assays

Assessment of KCNQ2/3 Channel Activation Activity

Biological activities of the compounds of the application can beassessed by using various methods known in the art. For example, theKCNQ2/3 channel activation activity of the compounds of the applicationcan be evaluated through an in vitro assay described below.

The in vitro effects of a compound of the application on cloned KCNQ2/3potassium channels (e.g., encoded by the human KCNQ2/3 gene) areevaluated using a patch clamp system. Compounds of the application aretested at various concentrations (e.g., 0.01, 0.1, 1, 10 and 100 μM) fora certain duration of exposure (e.g., 5 min). The baseline for eachrecording is established. A single test compound concentration isapplied for a certain duration of exposure after the vehicle. Eachrecording ends with treatment with a supramaximal dose of linopirdine.The % activation is calculated using the following equation by usingleak subtracted responses:

$\frac{{vehicle\_ response} - {compound\_ response}}{{vehicle\_ response} - {flupirtine\_ response}}$Maximal Electroshock Seizure Test (MES)

In MES test, the ability of different doses of the test compound inpreventing seizure induced by an electrical stimulus, delivered throughthe corneal electrodes primed with a drop of anesthetic/electrolytesolution is tested. Mice are restrained and released immediatelyfollowing corneal stimulation that allows for the observation of theentire seizure episode. A maximal seizure in a test animal includes fourdistinct phases that includes, hind leg flexor component tonic phase(Phase I), hind leg extensor component of the tonic phase (Phase II),intermittent, whole-body clonus (Phase III), and muscular relaxation(Phase IV) followed by seizure termination (Woodbury & Davenport, 1952;Racine et al., 1972). Test compounds are tested for their ability toabolish hind limb tonic extensor component that indicates the compound'sability to inhibit MES-induced seizure spread. Compounds arepre-administered (i.p) and tested at various time points for theabolishment of hind limb tonic extensor component after electricalstimulus.

Corneal-Kindled Mouse Model of Partial Seizures

In corneal kindled seizure model, mice are kindled electrically withstimulation delivered through corneal electrodes primed with tetracainehydrochloride in saline, twice daily, until 5 consecutive stage Vseizures are induced. Mice are considered kindled when they display atleast 5 consecutive stage V seizures according to the Racine scale(Racine et al., 1972) including, mouth and facial clonus (stage I),Stage I plus head nodding (Stage II), Stage II plus forelimb clonus(Stage III), Stage III plus rearing (Stage IV), and stage IV plusrepeated rearing and falling (Stage V) (Racine et al., 1972). At thecompletion of the kindling acquisition, mice are permitted a 3-daystimulation-free period prior to any drug testing. On the day of theexperiment, fully kindled mice are pre-administered (i.p) withincreasing doses of the test compound and challenged with the cornealkindling stimulus. Mice are scored as protected (seizure score of <3) ornot protected, (seizure score≥4) based on the Racine scoring (Racine etal., 1972).

Pharmaceutical Compositions

The present application relates to pharmaceutical compositionscomprising a compound of the application as an active ingredient. In oneembodiment, the application provides a pharmaceutical compositioncomprising at least one compound of each of the formulae describedherein, or a pharmaceutically acceptable salt or solvate thereof, andone or more pharmaceutically acceptable carriers or excipients. In oneembodiment, the application provides a pharmaceutical compositioncomprising at least one compound selected from Table 1.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the application can be formulated for oraladministration in forms such as tablets, capsules (each of whichincludes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. The compounds of the application can also be formulated forintravenous (bolus or in-fusion), intraperitoneal, topical,subcutaneous, intramuscular or transdermal (e.g., patch) administration,all using forms well known to those of ordinary skill in thepharmaceutical arts.

The formulation of the present application may be in the form of anaqueous solution comprising an aqueous vehicle. The aqueous vehiclecomponent may comprise water and at least one pharmaceuticallyacceptable excipient. Suitable acceptable excipients include thoseselected from the group consisting of a solubility enhancing agent,chelating agent, preservative, tonicity agent, viscosity/suspendingagent, buffer, and pH modifying agent, and a mixture thereof.

Any suitable solubility enhancing agent can be used. Examples of asolubility enhancing agent include cyclodextrin, such as those selectedfrom the group consisting of hydroxypropyl-β-cyclodextrin,methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin,ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin,peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin,2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin,glucosyl-β-cyclodextrin, sulphated β-cyclodextrin (S-β-CD),maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether,branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomlymethylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixturesthereof.

Any suitable chelating agent can be used. Examples of a suitablechelating agent include those selected from the group consisting ofethylenediaminetetraacetic acid and metal salts thereof, disodiumedetate, trisodium edetate, and tetrasodium edetate, and mixturesthereof.

Any suitable preservative can be used. Examples of a preservativeinclude those selected from the group consisting of quaternary ammoniumsalts such as benzalkonium halides (preferably benzalkonium chloride),chlorhexidine gluconate, benzethonium chloride, cetyl pyridiniumchloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate,phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben,sorbic acid, potassium sorbate, sodium benzoate, sodium propionate,ethyl p-hydroxybenzoate, propylaminopropyl biguanide, andbutyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

The aqueous vehicle may also include a tonicity agent to adjust thetonicity (osmotic pressure). The tonicity agent can be selected from thegroup consisting of a glycol (such as propylene glycol, diethyleneglycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol,potassium chloride, and sodium chloride, and a mixture thereof.

The aqueous vehicle may also contain a viscosity/suspending agent.Suitable viscosity/suspending agents include those selected from thegroup consisting of cellulose derivatives, such as methyl cellulose,ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such aspolyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acidpolymers (carbomers), such as polymers of acrylic acid cross-linked withpolyalkenyl ethers or divinyl glycol (Carbopols—such as Carbopol 934,Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and amixture thereof.

In order to adjust the formulation to an acceptable pH (typically a pHrange of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5,particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), theformulation may contain a pH modifying agent. The pH modifying agent istypically a mineral acid or metal hydroxide base, selected from thegroup of potassium hydroxide, sodium hydroxide, and hydrochloric acid,and mixtures thereof, and preferably sodium hydroxide and/orhydrochloric acid. These acidic and/or basic pH modifying agents areadded to adjust the formulation to the target acceptable pH range. Henceit may not be necessary to use both acid and base—depending on theformulation, the addition of one of the acid or base may be sufficientto bring the mixture to the desired pH range.

The aqueous vehicle may also contain a buffering agent to stabilize thepH. When used, the buffer is selected from the group consisting of aphosphate buffer (such as sodium dihydrogen phosphate and disodiumhydrogen phosphate), a borate buffer (such as boric acid, or saltsthereof including disodium tetraborate), a citrate buffer (such ascitric acid, or salts thereof including sodium citrate), andε-aminocaproic acid, and mixtures thereof.

The formulation may further comprise a wetting agent. Suitable classesof wetting agents include those selected from the group consisting ofpolyoxypropylene-polyoxyethylene block copolymers (poloxamers),polyethoxylated ethers of castor oils, polyoxyethylenated sorbitanesters (polysorbates), polymers of oxyethylated octyl phenol(Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acidglyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters,and mixtures thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

Methods of Use

The present application relates to methods for the use of compounds ofthe application. The compounds of the application have a usefulpharmacological activity spectrum and are therefore particularlysuitable for the prophylaxis and/or treatment of diseases or disorders.

The present application provides a method of treating or preventingdiseases or disorders, comprising administering a therapeuticallyeffective amount of a compound of the application, or a pharmaceuticallyacceptable salt or solvate thereof, to a subject in need thereof. Thepresent application also provides the use of a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for administration to a subject forthe treatment or prevention of diseases or disorders. The presentapplication also provides a compound of the application, or apharmaceutically acceptable salt or solvate thereof, for treating orpreventing diseases or disorders.

In one embodiment, the disease or disorder is a condition which can beameliorated by KCNQ2/3 potassium channel opening. In one embodiment, thedisease or disorder is selected from epilepsy, neurotransmissiondisorder, CNS disorder, neurodegenerative disease (e.g., Alzheimer'sdisease, ALS, motor neuron disease, Parkinson's disease, maculardegeneration, or glaucoma), cognitive disorder (e.g., degenerativedementia (including senile dementia, Alzheimer's disease, Pick'sdisease, Huntington's chorea, Parkinson's disease, and Creutzfeldt-Jakobdisease); vascular dementia (including multi-infarct dementia); dementiaassociated with intracranial space occupying lesions, trauma, infectionsor related conditions (including HIV infection), metabolism, toxins,anoxia, or vitamin deficiency; mild cognitive impairment associated withageing, particularly Age Associated Memory Loss, or learningdeficiencies), bipolar disorder (e.g., Type I or II bipolar disorder),unipolar depression, anxiety, migraine, ataxia, myokimia, tinnitus,functional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac chestpain, or irritable bowel syndrome), cancer, inflammatory disease,ophthalmic disease (e.g., retinitis, retinopathies, uveitis, or acuteinjury to the eye tissue), asthma, allergic rhinitis, respiratorydistress syndrome, gastrointestinal conditions (e.g., inflammatory boweldisease, Chron's disease, gastritis, irritable bowel syndrome, orulcerative colitis), and inflammation in such diseases as vasculardisease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia,Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis,multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome,polymyositis, gingivitis, conjunctivitis, and myocardial ischemia.

In one embodiment, the application provides a method of producing ananti-epileptic, muscle relaxing, fever reducing, peripherallyanalagesic, and/or anti-convulsive effect in a subject in need thereof,comprising administering to the subject an effective amount of acompound of the application, or a pharmaceutically acceptable salt orsolvate thereof. The present application also provides the use of acompound of the application, or a pharmaceutically acceptable salt orsolvate thereof, for the preparation of a medicament for administrationto a subject for producing an anti-epileptic, muscle relaxing, feverreducing, peripherally analagesic, and/or anti-convulsive effect. Thepresent application also provides a compound of the application, or apharmaceutically acceptable salt or solvate thereof, for producing ananti-epileptic, muscle relaxing, fever reducing, peripherallyanalagesic, and/or anti-convulsive effect.

In one embodiment, the application provides compounds that are useful asan anti-convulsant. They are therefore useful in treating or preventingepilepsy. Compounds of the application may be used to improve thecondition of a host, typically a human being, suffering from epilepsy.They may be employed to alleviate the symptoms of epilepsy in a host.“Epilepsy” is intended to include the following seizures: simple partialseizures, complex partial seizures, secondary generalized seizures,generalized seizures including absence seizures, myoclonic seizures,clonic seizures, tonic seizures, tonic clonic seizures and atonicseizures. Partial-onset seizures are the most common type of seizure inadult patients. For partial seizures, there is a focal epileptic zone(site of seizure onset), and seizure activity is initially limited toone hemisphere. Partial seizures can be further sub-divided into simplepartial (without impairment of consciousness), complex partial (withimpairment of consciousness with or following a simple partial onset)and secondarily generalized (i.e., partial seizures, either simple orcomplex, which evolve to generalized tonic-clonic seizures). Simplepartial seizures, depending on the anatomical site of origin of theseizure, may have motor, somatosensory or special sensory, autonomic orpsychic signs or symptoms.

In one embodiment, the application provides a method of treating asubject suffering from or susceptible to epilepsy, comprisingadministering to the subject an effective amount of a compound of theapplication or a pharmaceutically acceptable salt or solvate thereof.The present application also provides the use of a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for administration to a subjectsuffering from or susceptible to epilepsy for the treatment of epilepsy.The present application also provides a compound of the application, ora pharmaceutically acceptable salt or solvate thereof, for treating asubject suffering from or susceptible to epilepsy.

In one embodiment, the application provides a method for the adjunctivetreatment of adults with partial-onset seizures, comprisingadministering to the subject an effective amount of a compound of theapplication or a pharmaceutically acceptable salt thereof. The presentapplication also provides the use of a compound of the application, or apharmaceutically acceptable salt or solvate thereof, for the preparationof a medicament for adjunctive treatment of adults with partial-onsetseizures. The present application also provides a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for adjunctive treatment of adults with partial-onset seizures.

In one embodiment, the present application provides a method of treatingor preventing epilepsy, comprising administering a therapeuticallyeffective amount of a compound of the application, or a pharmaceuticallyacceptable salt or solvate thereof, to a subject in need thereof.

The present application also provides the use of a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for administration to a subject forthe treatment or prevention of epilepsy. The present application alsoprovides a compound of the application, or a pharmaceutically acceptablesalt or solvate thereof, for treating or preventing epilepsy.

In one embodiment, a compound of the application is administered incombination with one or more anti-epileptic drugs (AEDs). There aredifferent types of AEDs. For example, narrow-spectrum AEDs includephenytoin (Dilantin), phenobarbital, carbamazepine (Tegretol),oxcarbazepine (Trileptal), gabapentin (Neurontin), pregabalin (Lyrica),lacosamide (Vimpat), and vigabatrin (Sabril). Broad spectrum AEDsinclude valproic acid (Depakote), lamotrigine (Lamictal), topiramate(Topamax), zonisamide (Zonegran), levetiracetam (Keppra), clonazepam(Klonopin), and rufinamide (Banzel). In one embodiment, the AED is anyAED. In one embodiment, the AED is a narrow spectrum AED. In oneembodiment, the AED is a broad spectrum AED.

In one embodiment, the application provides compounds that are useful asanalgesics. The compounds are therefore useful in treating or preventingpain. They may be used to improve the condition of a host, typically ahuman being, suffering from pain. They may be employed to alleviate painin a host. Thus, the compounds may be used as a pre-emptive analgesic totreat acute pain such as musculoskeletal pain, post-operative pain andsurgical pain, chronic pain such as chronic inflammatory pain (e.g.,rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g., postherpetic neuralgia, trigeminal neuralgia and sympathetically maintainedpain) and pain associated with cancer and fibromyalgia. The compoundsmay also be used in the treatment or prevention of pain associated withmigraine. The compounds may also be used in the treatment of the pain(both chronic and acute), fever and inflammation of conditions such asrheumatic fever; symptoms associated with influenza or other viralinfections, such as the common cold; lower back and neck pain; headache;toothache; sprains and strains; myositis; neuralgia; synovitis;arthritis, including rheumatoid arthritis; degenerative joint diseases,including osteoarthritis; gout and ankylosing spondylitis; tendinitis;bursitis; skin related conditions, such as psoriasis, eczema, burns anddermatitis; injuries, such as sports injuries and those arising fromsurgical and dental procedures.

In one embodiment, the application provides a method of producing ananalgesic effect in a subject in need thereof, comprising administeringto the subject an effective amount of a compound of the application or apharmaceutically acceptable salt or solvate thereof. The presentapplication also provides the use of a compound of the application, or apharmaceutically acceptable salt or solvate thereof, for the preparationof a medicament for administration to a subject for producing ananalgesic effect. The present application also provides a compound ofthe application, or a pharmaceutically acceptable salt or solvatethereof, for producing an analgesic effect. In one embodiment, theanalgesic effect is a neuroprotective effect. In one embodiment, theanalgesic effect is a centrally acting analgesic effect.

In one embodiment, the application provides a method of treating orpreventing a neurotransmission disorder, CNS disorder, neurodegenerativedisease (e.g., Alzheimer's disease, ALS, motor neuron disease,Parkinson's disease, macular degeneration and glaucoma), cognitivedisorder, bipolar disorder (e.g., Type I or II bipolar disorder),unipolar depression, or anxiety in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound of theapplication or a pharmaceutically acceptable salt or solvate thereof.The present application also provides the use of a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for administration to a subject fortreating or preventing a neurotransmission disorder, CNS disorder,neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neurondisease, Parkinson's disease, macular degeneration and glaucoma),cognitive disorder, bipolar disorder (e.g., Type I or II bipolardisorder), unipolar depression, or anxiety. The present application alsoprovides a compound of the application, or a pharmaceutically acceptablesalt or solvate thereof, for treating or preventing a neurotransmissiondisorder, CNS disorder, neurodegenerative disease (e.g., Alzheimer'sdisease, ALS, motor neuron disease, Parkinson's disease, maculardegeneration and glaucoma), cognitive disorder, bipolar disorder (e.g.,Type I or II bipolar disorder), unipolar depression, or anxiety.

In one embodiment, the application provides a method of treating orpreventing migraine, ataxia, myokimia, tinnitus, and functional boweldisorders (e.g., non-ulcer dyspepsia, non-cardiac chest pain, orirritable bowel syndrome) in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound of theapplication or a pharmaceutically acceptable salt or solvate thereof.The present application also provides the use of a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for administration to a subject fortreating or preventing migraine, ataxia, myokimia, tinnitus, andfunctional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac chestpain, or irritable bowel syndrome). The present application alsoprovides a compound of the application, or a pharmaceutically acceptablesalt or solvate thereof, for treating or preventing migraine, ataxia,myokimia, tinnitus, and functional bowel disorders (e.g., non-ulcerdyspepsia, non-cardiac chest pain, or irritable bowel syndrome).

In one embodiment, the application provides compounds that are useful inthe treatment of CNS disorders such as bipolar disorder, alternativelyknown as manic depression. The compounds may thus be used to improve thecondition of a human patient suffering from bipolar disorder. They maybe used to alleviate the symptoms of bipolar disorder in a host. Thecompounds may also be used in the treatment of unipolar depression,ataxia, myokimia and anxiety.

In one embodiment, the application provides compounds that are useful inthe treatment of neurodegenerative diseases, such as Alzheimer'sdisease, ALS, motor neuron disease, Parkinson's disease, maculardegeneration and glaucoma. The compounds of the application may also beuseful in neuroprotection and in the treatment of neurodegenerationfollowing stroke, cardiac arrest, pulmonary bypass, traumatic braininjury, spinal cord injury or the like. In one embodiment, compounds ofthe application are further useful in the treatment of tinnitus.

In one embodiment, the application provides compounds that are useful inthe treatment of functional bowel disorders which include non-ulcerdyspepsia, non-cardiac chest pain and in particular irritable bowelsyndrome. Irritable bowel syndrome is a gastrointestinal disordercharacterized by the presence of abdominal pain and altered bowel habitswithout any evidence of organic disease. The compounds may thus be usedto alleviate pain associated with irritable bowel syndrome. Thecondition of a human patient suffering from irritable bowel syndrome maythus be improved.

In one embodiment, the application provides a method of preventing orreducing dependence on, or preventing or reducing tolerance, or reversetolerance, to a dependence-inducing agent in a subject in need thereof,comprising administering to the subject an effective amount of acompound of the application or a pharmaceutically acceptable salt orsolvate thereof. The present application also provides the use of acompound of the application, or a pharmaceutically acceptable salt orsolvate thereof, for the preparation of a medicament for administrationto a subject for preventing or reducing dependence on, or preventing orreducing tolerance, or reverse tolerance, to a dependence-inducingagent. The present application also provides a compound of theapplication, or a pharmaceutically acceptable salt or solvate thereof,for preventing or reducing dependence on, or preventing or reducingtolerance, or reverse tolerance, to a dependence-inducing agent.Examples of dependence inducing agents include opioids (e.g., morphine),CNS depressants (e.g., ethanol), psychostimulants (e.g., cocaine) andnicotine.

In one embodiment, the application provides a method of treating orpreventing cancer, inflammatory disease, or ophthalmic disease in asubject in need thereof comprising administering to the subject aneffective amount of a compound of the application or a pharmaceuticallyacceptable salt or solvate thereof. The present application alsoprovides the use of a compound of the application, or a pharmaceuticallyacceptable salt or solvate thereof, for the preparation of a medicamentfor administration to a subject for treating or preventing cancer,inflammatory disease, or ophthalmic disease. The present applicationalso provides a compound of the application, or a pharmaceuticallyacceptable salt or solvate thereof, for treating or preventing cancer,inflammatory disease, or ophthalmic disease.

In one embodiment, the application provides compounds that inhibitcellular and neoplastic transformation and metastatic tumor growth andhence are useful in the treatment of certain cancerous diseases, such ascolonic cancer.

In one embodiment, the application provides compounds that inhibitinflammatory processes and therefore are of use in the treatment ofasthma, allergic rhinitis and respiratory distress syndrome;gastrointestinal conditions such as inflammatory bowel disease, Chron'sdisease, gastritis, irritable bowel syndrome and ulcerative colitis; andthe inflammation in such diseases as vascular disease, migraine,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis,sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis,gingivitis, conjunctivitis and myocardial ischemia.

In one embodiment, the application provides compounds that are useful inthe treatment of ophthalmic diseases such as retinitis, retinopathies,uveitis, and acute injury to the eye tissue.

In one embodiment, the application provides compounds that are usefulfor the treatment of cognitive disorders such as dementia, particularlydegenerative dementia (including senile dementia, Alzheimer's disease,Pick's disease, Huntington's chorea, Parkinson's disease andCreutzfeldt-Jakob disease), and vascular dementia (includingmulti-infarct dementia), as well as dementia associated withintracranial space occupying lesions, trauma, infections and relatedconditions (including HIV infection), metabolism, toxins, anoxia andvitamin deficiency; and mild cognitive impairment associated withageing, particularly Age Associated Memory Loss; and learningdeficiencies.

In one embodiment, the application provides a method of producing ananxiolytic effect in a subject in need thereof comprising administeringto the subject an effective amount of a compound of the application or apharmaceutically acceptable salt or solvate thereof. In one embodiment,the application provides a method for the treatment of anxiety and itsrelated psychological and physical symptoms. Anxiolytics have been shownto be useful in the treatment of anxiety disorders. The presentapplication also provides the use of a compound of the application, or apharmaceutically acceptable salt or solvate thereof, for the preparationof a medicament for administration to a subject for producing ananxiolytic effect. The present application also provides a compound ofthe application, or a pharmaceutically acceptable salt or solvatethereof, for producing an anxiolytic effect.

In one embodiment, the application provides compounds for treatment. Inone embodiment, the application provides compounds for prophylaxis. Inone embodiment, the application provides compound for alleviation ofestablished symptoms.

Administration may for example be in the form of tablets, capsules,pills, coated tablets, suppositories, ointments, gels, creams, powders,dusting powders, aerosols or in liquid form. Liquid application formsthat may for example be considered are: oils or alcoholic or aqueoussolutions as well as suspensions and emulsions. In one embodiment, theapplication provides forms of application that are tablets that containbetween 30 and 60 mg or solutions that contain between 0.1 to 5 percentby weight of active substance.

In one embodiment, a compound of the application is used in humanmedicine. In one embodiment, the compound of the application is used inveterinary medicine. In one embodiment, a compound of the application isused in agriculture. In one embodiment, a compound of the application isused alone or mixed with other pharmacologically active substances.

The following Examples are illustrative and should not be interpreted inany way so as to limit the scope of the application.

EXAMPLES Example 1: Synthesis of Compound 16-fluoro-2-(2,3,5,6-tetrafluoro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline

Under air, to 1,2,3,4,5-pentafluoro-6-nitro-benzene (2.13 g, 10.0 mmol,1.00 equiv) in DMSO (5 mL) at 0° C. were added6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.51 g, 10.0 mmol, 1.00 equiv)and Et₃N (1.67 mL, 12.0 mmol, 1.20 equiv). After stirring for 30 min at23° C., the reaction mixture was diluted with EtOAc (30 mL), washed withwater (3×30 mL) and brine (30 mL), and dried (MgSO₄). The filtrate wasconcentrated in vacuo and the residue was triturated with Et₂O to afford2.40 g of the title compound (70% yield).

NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 23° C., δ): 7.04 (dd, J=7.8,5.4 Hz, 1H), 6.96-6.87 (m, 2H), 4.59 (s, 2H), 3.67 (t, J=6.0 Hz, 2H),3.02 (d, J=6.0 Hz, 2H).

2-(2,6-difluoro-3,5-dimethyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

Under nitrogen, to methyltriphenylphosphonium bromide (24.9 g, 69.7mmol, 10.0 equiv) in THF (350 mL) at 23° C. was added NaH (1.67 g, 69.7mmol, 10.0 equiv). After stirring for 24 hr at 60° C., the reactionmixture was cooled to 23° C. and6-fluoro-2-(2,3,5,6-tetrafluoro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline(2.40 g, 6.97 mmol, 1.00 equiv) was added. After stirring for 48 hr at60° C., the reaction mixture was cooled to 23° C. and water (500 mL) wasadded dropwise. The phases were separated and the aqueous phase wasextracted with EtOAc (2×300 mL). The combined organic phases were washedwith brine (300 mL) and dried (MgSO₄). The filtrate was concentrated invacuo and the residue was purified by column chromatography on silicagel eluting with hexanes/EtOAc to afford 1.80 g of the title compound(77% yield).

NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 23° C., δ): 7.01 (dd, J=7.8,5.4 Hz, 1H), 6.92-6.85 (m, 2H), 4.39 (s, 2H), 3.49 (t, J=6.0 Hz, 2H),2.90 (d, J=6.0 Hz, 2H), 2.19 (s, 6H).

3,5-difluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylaniline

Under air, to2-(2,6-difluoro-3,5-dimethyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline(1.90 g, 5.65 mmol, 1.00 equiv) in MeOH (57 mL) at 23° C. were added Znpowder (1.85 g, 28.3 mmol, 5.00 equiv) and NH₄Cl (1.51 g, 28.3 mmol,5.00 equiv) in H₂O (10 mL). After stirring for 1.5 hr at 23° C., thereaction mixture was filtered through a pad of celite. The filtrate wasconcentrated in vacuo, and H₂O (100 mL) and EtOAc (100 mL) were added tothe residue. The phases were separated and the aqueous phase wasextracted with EtOAc (2×100 mL). The combined organic phases were washedwith brine (200 mL) and dried (MgSO₄). The filtrate was concentrated invacuo to afford crude aniline, which was used in the next step withoutfurther purification.

N-(3,5-difluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 1)

Under nitrogen, to3,5-difluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylanilineobtained above in MeCN (6 mL) at 0° C. were added DIPEA (1.48 mL, 8.48mmol, 1.50 equiv) and tert-butylacetyl chloride (1.18 mL, 8.48 mmol,1.50 equiv). After stirring for 1 hr at 23° C., the reaction mixture wasconcentrated in vacuo, and the residue was purified by columnchromatography on silica gel eluting with hexanes/EtOAc to afford 1.00 gof the title compound (44% yield over 2 steps).

NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 23° C., δ): 6.98 (dd, J=7.8,5.4 Hz, 1H), 6.90-6.80 (m, 2H), 6.64 (s, 1H), 4.30 (s, 2H), 3.43 (t,J=6.0 Hz, 2H), 2.95 (d, J=6.0 Hz, 2H), 2.30 (s, 2H), 2.10 (s, 6H), 1.16(s, 9H).

Example 2: Synthesis of Compound 22,3,5,6-tetrafluoro-N-(4-fluorobenzyl)-4-nitroaniline

Under air, to 1,2,3,4,5-pentafluoro-6-nitro-benzene (2.13 g, 10.0 mmol,1.00 equiv) in DMSO (5 mL) at 0° C. were added 4-fluorobenzylamine (1.25g, 10.0 mmol, 1.00 equiv) and Et₃N (1.67 mL, 12.0 mmol, 1.20 equiv).After stirring for 30 min at 23° C., the reaction mixture was dilutedwith EtOAc (30 mL), washed with water (3×30 mL) and brine (30 mL), anddried (MgSO₄). The filtrate was concentrated in vacuo and the residuewas purified by chromatography on silica gel eluting with hexanes/EtOActo afford 1.85 g of the title compound (58% yield).

NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 23° C., δ): 7.30 (dd, J=8.4,5.4 Hz, 2H), 7.08 (dd, J=8.4, 8.4 Hz, 2H), 4.66 (s, 2H).

tert-butyl 4-fluorobenzyl(2,3,5,6-tetrafluoro-4-nitrophenyl)carbamate

Under nitrogen, to 2,3,5,6-tetrafluoro-N-(4-fluorobenzyl)-4-nitroaniline(1.85 g, 5.81 mmol, 1.00 equiv) in THF (35 mL) at 23° C. were added DMAP(71 mg, 0.58 mmol, 10 mol %), NaH (153 mg, 6.39 mmol, 1.10 equiv), andBoc₂O (1.47 mL, 6.39 mmol, 1.10 equiv). After stirring for 1.5 hr at 60°C., the reaction mixture was cooled to 23° C. and water (20 mL) wasadded dropwise. The phases were separated and the aqueous phase wasextracted with EtOAc (2×20 mL). The combined organic phases were washedwith brine (20 mL) and dried (MgSO₄). The filtrate was concentrated invacuo and the residue was purified by column chromatography on silicagel eluting with hexanes/EtOAc to afford 1.50 g of the title compound(62% yield).

NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 23° C., δ): 7.20 (dd, J=8.4,5.4 Hz, 2H), 6.98 (dd, J=8.4, 8.4 Hz, 2H), 4.81 (s, 2H), 1.44 (br s,9H).

tert-butyl (2,6-difluoro-3,5-dimethyl-4-nitrophenyl)(4-fluorobenzyl)carbamate

Under nitrogen, to methyltriphenylphosphonium bromide (12.8 g, 35.9mmol, 10.0 equiv) in THF (250 mL) at 23° C. was added NaH (862 mg, 35.9mmol, 10.0 equiv). After stirring for 24 hr at 60° C., the reactionmixture was cooled to 23° C. and tert-butyl4-fluorobenzyl(2,3,5,6-tetrafluoro-4-nitrophenyl)carbamate (1.50 g, 3.59mmol, 1.00 equiv) was added. After stirring for 48 hr at 60° C., thereaction mixture was cooled to 23° C. and water (300 mL) was addeddropwise. The phases were separated and the aqueous phase was extractedwith EtOAc (2×200 mL). The combined organic phases were washed withbrine (300 mL) and dried (MgSO₄). The filtrate was concentrated in vacuoand the residue was purified by column chromatography on silica geleluting with hexanes/EtOAc to afford 1.06 g of the title compound (72%yield).

NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 23° C., δ): 7.22-7.18 (m, 2H),7.02-6.89 (m, 2H), 4.73 (s, 2H, major isomer), 4.67 (s, 2H, minorisomer), 2.14 (br s, 6H), 1.50 (s, 9H, minor isomer), 1.39 (s, 9H, majorisomer). *A mixture of rotational isomers was observed in the NMR timescale, which complicated the further structural analysis.

tert-butyl (4-amino-2,6-difluoro-3,5-dimethylphenyl)(4-fluorobenzyl)carbamate

Under air, to2-(2,6-difluoro-3,5-dimethyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline(1.06 g, 2.58 mmol, 1.00 equiv) in MeOH (26 mL) at 23° C. were added Znpowder (844 mg, 12.9 mmol, 5.00 equiv) and NH₄Cl (690 mg, 12.9 mmol,5.00 equiv) in H₂O (5 mL). After stirring for 1.5 hr at 23° C., thereaction mixture was filtered through a pad of celite. The filtrate wasconcentrated in vacuo, and H₂O (100 mL) and EtOAc (100 mL) were added tothe residue. The phases were separated and the aqueous phase wasextracted with EtOAc (2×100 mL). The combined organic phases were washedwith brine (200 mL) and dried (MgSO₄). The filtrate was concentrated invacuo to afford crude aniline, which was used in the next step withoutfurther purification.

tert-butyl (4-(3,3-dimethylbutanamido)-2,6-difluoro-3,5-dimethylphenyl)(4-fluorobenzyl)carbamate

Under nitrogen, to tert-butyl(4-amino-2,6-difluoro-3,5-dimethylphenyl)(4-fluorobenzyl)carbamateobtained above in MeCN (4 mL) at 0° C. were added DIPEA (0.674 mL, 3.87mmol, 1.50 equiv) and tert-butylacetyl chloride (0.538 mL, 3.87 mmol,1.50 equiv). After stirring for 1 hr at 23° C., the reaction mixture wasconcentrated in vacuo to afford crude acylation product, which was usedin the next step without further purification.

N-(3,5-difluoro-4-((4-fluorobenzyl)amino)-2,6-dimethylphenyl)-3,3-dimethylbutanamide(Compound 2)

Under nitrogen, to tert-butyl(4-(3,3-dimethylbutanamido)-2,6-difluoro-3,5-dimethylphenyl)(4-fluorobenzyl)carbamateobtained above in DCM (13 mL) at 23° C. was added HCl (2.0 M in Et₂O,12.9 mL, 25.8 mmol, 10.0 equiv). After stirring for 3 hr at 23° C.,NaHCO₃ (aq) (20 mL) was added to the reaction mixture. The phases wereseparated and the aqueous phase was extracted with EtOAc (2×20 mL). Thecombined organic phases were washed with brine (20 mL) and dried(MgSO₄). The filtrate was concentrated in vacuo and the residue waspurified by column chromatography on silica gel eluting withhexanes/EtOAc to afford 670 mg of the title compound (69% yield over 3steps).

NMR Spectroscopy: ¹H NMR (300 MHz, methanol-d4, 23° C., δ): 7.31 (dd,J=8.4, 5.4 Hz, 2H), 6.98 (dd, J=8.4, 8.4 Hz, 2H), 4.40 (s, 2H), 2.27 (s,2H), 2.02 (br s, 6H), 1.10 (s, 9H).

Example 3: Synthesis of Compound 3

Compound 3 is synthesized in a similar way as Compound 1 using thecorresponding commercially available 4-methoxypiperidine in place of6-fluoro-1,2,3,4-tetrahydroisoquinoline.

Example 4: Synthesis of Compound 4

Compound 4 is synthesized in a similar way as Compound 1 using thecorresponding commercially available ethyltriphenylphosphonium bromidein place of methyltriphenylphosphonium bromide.

Example 5: Synthesis of Compound 5

Compound 5 is synthesized in a similar way as Compound 2 using thecorresponding commercially available ethyltriphenylphosphonium bromidein place of methyltriphenylphosphonium bromide.

Example 6: Synthesis of Compound 6

Compound 6 is synthesized in a similar way as Compound 3 using thecorresponding commercially available ethyltriphenylphosphonium bromidein place of methyltriphenylphosphonium bromide.

Example 7: Assessment of Recombinantly Expressed Human Kv7.2/7.3Channels Activation Ability

The in vitro effects of a compound of the present applicationrecombinantly expressed human Kv7.2/7.3 channels are assessed onSyncropatch high throughput electrophysiology platform.

Cell Preparations:

CHO cells stably expressing human Kv7.2/7.3 channels were cultured inHam's F-12 media (Hyclone, Cat # SH30022.02) supplemented with 10% FetalBovine Serum, 1×MEM non-essential amino acids, and 400 μg/ml G418 at 37°C. in 5% CO₂. On the day of Syncropatch, the cells were washed once inDPBS (Hyclone, Cat # SH30028.03) for approximately 30 seconds. 1 ml of1×0.015% Trypsin-EDTA GIBCO Cat #25300-054) was added and swirled aroundto cover the bottom of the flask, and allowed to sit on the cells forabout 4 minutes (approximately 90% of the cells were lifted by lighttapping of the flask). 10 ml of cold media (Ham's F-12 media (Hyclone,Cat # SH30022.02) supplemented with 10% Fetal Bovine Serum, 1×MEMnon-essential amino acids, and 400 μg/ml G418) was added to inactivateTrypsin. The cells were then triturated until a single cell suspensionwas achieved, and the cell count was performed. The cells were thendiluted to a concentration of 5×10⁵/ml and placed into the “cell hotel”on the deck of the Syncropatch at 10° C. for about 1 hour to recover. 40μL of the cell suspension was dispensed into each well of a 384-wellSyncropatch chip by the onboard pipettor at the beginning of eachSyncropatch assay.

Test Solution Preparations.

The compounds to be tested were dissolved in DMSO to give 10 mM stocksolutions. Eight-point dose response curves were created by performingsemi-log serial dilutions from 10 mM compound stock solutions in 100%DMSO. Concentration-response curves were transferred to assay plates togive two-fold final compound concentration to account for the two-folddilution with drug addition on the SyncroPatch. Final DMSO concentrationin the assay was 0.3%. Final assay test concentrations were 30 μM to0.01 μM or 1 μM to 0.0003 μM. Negative (0.3% DMSO) and positive (30 μMML213) controls were included in each test run to assess pharmacologicalresponsiveness.

Assessment Protocol:

Electrophysiological studies of the compounds were performed using theNanion SyncroPatch automated patch clamp platform. Compound effects onKv7 channels were assayed using a voltage protocol as shown in FIG. 1.

Kv7 channels were evaluated using a voltage protocol in which cells werevoltage-clamped at a holding potential of −110 mV. Potassium currentswere activated with a series of voltage steps from −110 mV to +50 mV in10 mV intervals with 5.5 seconds between successive voltage steps. Eachvoltage step was 3 seconds in duration and immediately followed by a 1second voltage step to −120 mV to generate an inward “tail” current toallow construction of activation (G-V) curves by plotting normalizedpeak tail current versus the potential of the activating voltage step.To obtain normalized values, peak current amplitudes for successivedepolarizing pulses were normalized against the maximum tail currentamplitude generated at +50 mV (Tatulian et al., Journal of Neuroscience2001, 21 (15)).

Data Analysis:

Data was collected on the Syncropatch platform using PatchControlsoftware (Nanion) and processed and analyzed using DataControl Software(Nanion). Normalized percent activation was calculated and activationcurves were fit with a Boltzmann function to determine the midpointvoltage of activation (G-V midpoint) for both pre-compound andpost-compound conditions for each of the 384-wells of a sealchip withPipeline Pilot (Accelrys). The difference in G-V midpoint betweenpre-compound and post-compound conditions (Δ V0.5) was plotted as afunction of concentration and concentration-response curves were fitwith a three-parameter logistic equation{Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}(Log EC50−X))} fordetermination of the EC₅₀ (Graphpad Prism).

Assessment Results:

Exemplary compounds of the present application were tested for theirability to produce a concentration-dependent hyperpolarizing shift inthe midpoint of activation for heteromeric Kv7.2/7.3 channels. Eight ofthe compounds produced a quantifiable hyperpolarizing shift inactivation as determined by a concentration-dependent shift in themidpoint that could be fit with a 3-parameter logistic equation. Thesedata were combined with the initial 8-point concentration-response datain a single fit. Potency and efficacy data for each compound aresummarized in Table 2.

TABLE 2 Selectivity KCNQ3/ KCNQ4 5 EC50 EC50 Compound KCNQ2/3 KCNQ3/5KCNQ4 KCNQ2/ KCNQ2/ No. EC₅₀ EC₅₀ EC₅₀ 3 EC50 3 EC50 Control A A B I IV1 B C D III VI 2 A B C IV V A: <0.1 μM, B: 0.1 to <1 μM, C: 1 to <10 μM,D: ≥10 μM. I: <1, II: 1 to <5, III: 5 to <10, IV: 10 to <50, V: 50 to<100, VI: ≥100.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A compound of formula A:

or a pharmaceutically acceptable salt or solvate thereof, wherein: X₁and X₉ are each independently methyl or ethyl; X₄ is H, C₁-C₄ alkyl,C₂-C₆ alkenyl, or C₂-C₆ alkynyl; X₅ is phenyl-(CX₈X₈)_(m), wherein thephenyl is optionally substituted with one or more substituentsindependently selected from deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkylsubstituted with one or more F, C₁-C₄ alkoxy, and C₁-C₄ alkoxysubstituted with one or more F; or X₄ and X₅, together with the nitrogenatom to which they are attached, form a 5- to 7-membered heterocyclicring comprising 1 or 2 heteroatoms selected from N, O, and S, whereinthe heterocyclic ring is optionally substituted with one or moresubstituents independently selected from deuterium, F, SF₅, C₁-C₄ alkyl,C₁-C₄ alkyl substituted with one or more F, C₁-C₄ alkoxy, and C₁-C₄alkoxy substituted with one or more F, or two substituents attached toadjacent carbon atoms on the heterocyclic ring, together with the carbonatoms to which they are attached, form a phenyl optionally substitutedwith one or more substituents independently selected from deuterium, F,SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one or more F, C₁-C₄alkoxy, and C₁-C₄ alkoxy substituted with one or more F; each X₅ isindependently H, deuterium, F, C₁-C₄ alkyl, or C₁-C₄ alkyl substitutedwith one or more F; and m is 1, 2, or
 3. 2. The compound of claim 1,being of formula Ia or Ib:

or a pharmaceutically acceptable salt or solvate thereof.
 3. Thecompound of claim 1, wherein X₄ is H.
 4. The compound of claim 1,wherein X₄ is C₁-C₄ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.
 5. Thecompound of claim 1, wherein X₅ is phenyl-(CX₈X₈), phenyl-(CX₈X₈)₂, orphenyl-(CX₈X₈)₃, wherein the phenyl is optionally substituted with oneor more substituents independently selected from deuterium, F, SF₅,C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one or more F, C₁-C₄ alkoxy,and C₁-C₄ alkoxy substituted with one or more F.
 6. The compound ofclaim 5, wherein X₅ is phenyl-(CX₈X₈).
 7. The compound of claim 5,wherein the phenyl is substituted with one or more substituentsindependently selected from F, CF₃, and OCF₃.
 8. The compound of claim1, wherein X₄ and X₅, together with the nitrogen atom to which they areattached, form a 5- to 7-membered heterocyclic ring comprising 1 or 2heteroatoms selected from N, O, and S, wherein the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substitutedwith one or more F, C₁-C₄ alkoxy, and C₁-C₄ alkoxy substituted with oneor more F.
 9. The compound of claim 8, wherein the heterocyclic ring issubstituted with one or more substituents independently selected fromCH₃ and OCH₃.
 10. The compound of claim 8, wherein the heterocyclic ringis pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl, dioxanyl,morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl.
 11. The compound ofclaim 1, wherein X₄ and X₅, together with the nitrogen atom to whichthey are attached, form a 5- to 7-membered heterocyclic ring substitutedwith two or more substituents, wherein two substituents attached toadjacent carbon atoms on the heterocyclic ring, together with the carbonatoms to which they are attached, form a phenyl optionally substitutedwith one or more substituents independently selected from deuterium, F,SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one or more F, C₁-C₄alkoxy, and C₁-C₄ alkoxy substituted with one or more F.
 12. Thecompound of claim 11, wherein X₄ and X₅, together with the nitrogen atomto which they are attached, form a heterocyclic ring selected from

wherein the nitrogen atom is the nitrogen atom bonded to X₄ and X₅. 13.The compound of claim 1, being of formula IIa or IIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein: X₄ isH, C₁-C₄ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; t1 is 1, 2, 3, 4, or 5;each Z₁ is independently selected from deuterium, F, SF₅, C₁-C₄ alkyl,C₁-C₄ alkyl substituted with one or more F, C₁-C₄ alkoxy, and C₁-C₄alkoxy substituted with one or more F; and m is 1, 2, or
 3. 14. Thecompound of claim 1, being of formula IIIa or IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein: q is1, 2, or 3; t2 is 1, 2, 3, or 4; and each Z₂ is independently selectedfrom deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one ormore F, C₁-C₄ alkoxy, and C₁-C₄ alkoxy substituted with one or more F.15. The compound of claim 1, being of formula IVa or IVb:

or a pharmaceutically acceptable salt or solvate thereof, wherein: r is1, 2, or 3; t3 is 1, 2, 3, or 4; and each Z₃ is independently selectedfrom deuterium, F, SF₅, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with one ormore F, C₁-C₄ alkoxy, and C₁-C₄ alkoxy substituted with one or more F.16. The compound of claim 1, being selected from the groups consistingof

and pharmaceutically acceptable salts and solvates thereof.
 17. Apharmaceutical composition comprising at least one compound of claim 1or a pharmaceutically acceptable salt or solvate thereof and one or morepharmaceutically acceptable carrier or excipient.